The present invention provides a novel composition of matter, 2-decarboxy-2-alkylcarbonyl-PG-type compounds. The present invention further provides for the use of these compounds as gastrointestinal cytoprotective agents. Moreover the present invention provides novel intermediates and processes for preparing such compounds.
The prostaglandins are a family of cyclic carboxylic acids, containing 20 carbon atoms. Typical of the prostaglandins is PGF.sub.2 .alpha., whose structure and carbon atom numbering are as depicted in formula I. ##STR1## For a discussion of the prostaglandins and their pharmacological effects, see Bergstrom, et al., Pharmacol. Review 20:1, and references cited therein.
The prostaglandins, such as PGF.sub.2 .alpha. are all named according to the degree of unsaturation exhibited in the side chains at C-8 and C-12 and the functional groups and/or unsaturation present on the cyclopentane ring. Accordingly, PGF.sub.2 .alpha. exhibits two double bonds (C-5 and C-13), while the corresponding PGF.sub.1 .alpha. exhibits a single double bond at C-13. When the stereochemistry of PGF.sub.2 .alpha. at C-9 is reversed, the resulting prostaglandins are of the PGF.beta. series, e.g., PGF.sub.2 .beta.. Likewise, a PGE compound such as PGE.sub.2 is similar to PGF.sub.2 .alpha. as depicted above except that the C-9 hydroxy is replaced by an oxo.
The various prostaglandins all exhibit one or more centers of asymmetry and thus can exist in either optically active or optically inactive (racemic) form. For example, PGF.sub.2 .alpha. as depicted above contains five centers of asymmetry: C-8, C-9, C-11, C-12, and C-15. For formula I above and the various formulas hereinafter substituents of asymmetric carbon atoms above the plane of the cyclopentane ring are depicted by heavy solid lines (the beta configuration), while dotted lines represent substituents below the plane of the cyclopentane ring (the alpha configuration). Thus for PGF.sub.2 .alpha. the asymmetric centers are respectively of the alpha, alpha, alpha, beta, and alpha configurations. When wavy lines are employed hereinafter (.about.), the substituents thereby depicted are either in the alpha or beta configuration or in a mixture of alpha and beta configurations.
The side chain hydroxyl at C-15 of PGF.sub.2 .alpha. is in the "S" configuration according to the Cahn-Ingold-Prelog sequence rules. See J. Chem. Ed. 41:16 (1964). Also, Nature 212:38 (1966) provides a discussion of the stereochemistry of the prostaglandins. Expressions such as C-8, C-9, C-11, C-12, C-15, and the like will hereinafter refer to the carbon atom in any prostaglandin or prostaglandin analog which is in the position corresponding to the position of the same number in PGF.sub.2 .alpha. above.
For convenience hereinafter the use of the term prostaglandin ("PG") will mean the optically active form of the prostaglandin thereby referred to with the same absolute configuration as PGF.sub.2 .alpha. obtained from mammalian sources. The term prostaglandin-type of PG-type product, as used herein, will refer to any monocyclic or bicyclic cyclopentane derivative herein which is pharmacologically useful. The formulas as drawn herein which depict a prostaglandin-type product or an intermediate useful in the preparation of a prostaglandin-type product each represent a particular stereoisomer which is of the same relative stereochemical configuration as the corresponding prostaglandin obtained from mammallian sources, or the particular stereoisomer of the intermediate which is useful in preparing the above stereoisomer of the PG-type product. The term prostaglandin analog, as used herein, represents that stereoisomer of a prostaglandin-type product which is of the same relative stereochemical configuration as a corresponding prostaglandin obtained from mammalian tissues or a mixture comprising that stereoisomer and the enantiomer thereof. In particular, where a formula is used to depict a prostaglandin-type product herein, the term "prostaglandin analog" refers to the compound of that formula or a mixture comprising that compound and the enantiomer thereof.
In addition to the naturally-occurring prostaglandins, certain chemical analogs thereof have been prepared and are known in the art. Among the prostaglandin analogs known in the art are the PGD-type, 9.beta.-PGD-type, and 9-deoxy-9,10-didehydro-PGD-type compounds of U.S. Pat. Nos. 4,016,184; the PGC-type compounds of 3,993,686, the 9-deoxy-9-methylene-PGF-type compounds of 4,021,467 and 4,060,534; the 11-deoxy-PG-type compounds of 4,029,693 and 3,987,072; the 8.beta.,12.alpha.-PG-type compounds of 3,979,483; the 2,2-difluoro-PG-type compounds of 4,001,300; the cis-4,5-didehydro-PG-type compounds of 4,032,561 and 3,933,889; the inter-phenylene-PG-type compounds of 4,020,097 and 3,997,566; the 5,6-didehydro-PG.sub.2 -type or 4,4,5,5-tetradehydro-PG.sub.1 -type compounds of 4,013,695; the 5-oxa-PG.sub.1 -type compounds of 3,931,279 and 3,864,387; the 4-oxa-PG.sub.1 -type and 3-oxa-PG.sub.1 -type compounds of 3,944,593,; the 13-cis-PG-type compounds of 4,026,909; the 13,14-didehydro-PG-type compounds of 4,029,681 and 4,018,803; the .omega.-aryl-PG-type compounds of 3,987,087; the .omega.-aryloxy-PG-type compounds of 3,864,387; the 16-alkyl-PG-type compounds of 3,903,131; the 16-fluoro-PG-type compounds of 3,962,293; and 15-methyl-PG-type compounds of 3,728,382.
While the naturally-occurring prostaglandins are carboxylic acids, numerous derivatives thereof are known in the art. For example, ester derivatives, including especially aromatic and phenacyl esters, are known in the art. See U.S. Pat. Nos. 3,069,332, 3,598,858, 3,979,440, and 3,984,062. Likewise, salts of these carboxylic acids are known in the art. See U.S. Pat. Nos. 3,069,332 and 3,958,858 cited above, as well as other references such as 3,657,327 and 3,888,916. Other derivatives of the prostaglandins, such as the amides thereof, are known in the art. See U.S. Pat. Nos. 3,853,941, 3,884,942, 3,903,299, 3,880,883, and 3,953,470.
Finally, there are also known macrocyclic lactone derivatives of the prostaglandins as is, for example, described by Corey, E. J. et al., JACS 97:653 (1975) and U.S. Pat. Nos. 3,931,206, 4,067,991, 4,049,648, 4,032,543, 4,045,449, and 4,049,678.
In addition to these various carbonyl-containing prostaglandin analogs, there are likewise known in the art acidic, non-carboxylic prostaglandin anlogs such as tetrazoles and sulfonates. See for example the 2-decarboxycarboxy-2-tetrazolyl-PG analogs described in U.S. Pat. Nos. 3,883,513, 3,932,389, 3,984,400, and 4,035,360. Also 2-decarboxy-2-sulfonyl-type compounds are described in U.S. Pat. No. 3,922,301.
Among the various other modifications at the C-2 position of the known prostaglandin analogs is the replacement of the carboxyl with an amine, as is for example described in U.S. Ser. No. 719,055, filed Aug. 30, 1976 and Derwent Farmdoc CPI No. 46957Y (abstracting Belgian Pat. No. 849,963).
Numerous references also describe primary alcohols corresponding to the known prostaglandins and analogs thereof as are described in U.S. Pat. Nos. 4,028,419, 4,055,602, 4,032,576, 3,931,207, 3,878,239, 3,966,792, 4,024,174, 3,962,312, 3,636,120, 3,723,528, 3,895,058, 3,954,881, 4,004,021, and 3,962,218. In addition to these 2-decarboxy-2-hydroxymethyl-PG compounds, there are known the corresponding C-2 aldehydes as described in U.S. Pat. Nos. 3,931,296 and 3,953,435. See also Derwent Farmdoc CPI No. 35953X and at 93049X for a description of further 2-decarboxy-2-carboxaldehyde-PG analogs. Finally, the C-2 acetals thereof are described at Derwent Farmdoc CPI No. 94924X.